A facile synthesis of N-benzyl-4-acetylproline via a tandem cationic aza-Cope rearrangement-Mannich reaction

Article abstract of DOI:10.1016/S0040-4039(01)02287-0

N-Benzyl-4-acetylproline can be prepared from N-(2-hydroxy-2-methyl)but-3-enyl-N-benzylamine and glyoxylic acid via a tandem cationic aza-Cope rearrangement-Mannich reaction. This reaction represents the first example of such a mechanism being utilised fo

Full text of DOI:10.1016/S0040-4039(01)02287-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 903–905
A facile synthesis of N-benzyl-4-acetylproline via a tandem
cationic aza-Cope rearrangement-Mannich reaction
Andrew Cooke,a,* Jonathan Bennetta and Emma McDaidb
aDepartment of Medicinal Chemistry, Organon Laboratories Ltd., Newhouse, Scotland ML1 5SH, UK
bDepartment of Chemistry, University of Edinburgh, West Mains Road, Edinburgh EH9 3JJ, UK
Received 15 October 2001; revised 20 November 2001; accepted 30 November 2001
Abstract—N-Benzyl-4-acetylproline can be prepared from N-(2-hydroxy-2-methyl)but-3-enyl-N-benzylamine and glyoxylic acid
via a tandem cationic aza-Cope rearrangement-Mannich reaction. This reaction represents the first example of such a mechanism
being utilised for the synthesis of functionalised proline derivatives. In addition the reaction requires only mild conditions and a
good yield of amino acid product is obtained without any need for purification. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
We hypothesised that a combination of this work and
the tandem cationic aza-Cope rearrangement-Mannich
cyclisation pioneered by Overman et al. would yield
N-benzyl-4-acetylproline.4
Substituted proline derivatives have been shown to
exhibit interesting biological activities, e.g. a-kainic
acid and domoic acid, which possess potent neuro-
pharmacological activity.1
A
number of synthetic
The tandem cationic aza-Cope rearrangement-Man-
nich cyclisation reaction as reported by Overman et
al. proceeds by iminium ion formation of a 2-
hydroxy-2-methylbut-3-enylamine 3 with an aldehyde
and subsequent 3,3 cationic aza-Cope rearrangement
to afford 3-acetylpyrrolidines 4 (Scheme 2). However,
in this case a nucleophilic substituent is incorporated
into the starting iminium ion. After the 3,3 aza-Cope
rearrangement, the nucleophilic substituent is
unleashed and irreversibly captures the desired rear-
ranged iminium ion giving 3-acetylpyrrolidine prod-
ucts.
strategies have been utilised to synthesise substituted
proline derivatives, including the cycloaddition of
azomethine ylides to olefinic dipolarophiles.2
We had identified N-benzyl-4-acetylproline as a novel
amino acid and interesting synthon for the prepara-
tion of pharmaceutically active analogues. We
recently reported the synthesis of N-benzylallylglycine
2 from N-benzylbut-3-enylamine 1 and glyoxylic acid
via the tandem aza-Cope rearrangement-iminium ion
hydrolysis reaction (Scheme 1).3 The rearrangement
requires
a subsequent reaction, in this case an
iminium ion hydrolysis, to drive the equilibrium to
the desired product.
Despite the extensive use of tandem cationic aza-Cope
rearrangements, there have been no reports published
Scheme 1. Synthesis of N-benzylallylglycine 2.
* Corresponding author. Tel.: +044-(0)1698-736136; fax: +044-(0)1698-736187; e-mail: a.cooke@organon.nhe.akzonobel.nl
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02287-0

904
A. Cooke et al. / Tetrahedron Letters 43 (2002) 903–905
Scheme 2. Synthesis of 3-acetylpyrrolidines 4.
utilising glyoxylic acid to yield functionalised proline
derivatives.4,5
Major isomer: An NOE correlation was observed
between the acetyl CH3 and hydrogen HB indicating
that the two groups were on the same side of the
five-membered ring. Also no NOE correlation was
observed between hydrogens HA and HB. It was there-
fore concluded that the major diastereomer had the
acid and acetyl groups trans to each other.
In this letter we wish to report the facile synthesis of the
novel N-benzyl-4-acetylproline 6 from N-(2-hydroxy-2-
methyl)but-3-enyl-N-benzylamine 5 and glyoxylic acid
via a tandem cationic aza-Cope rearrangement-Man-
nich reaction. This method requires only mild condi-
tions and yields pure products without the need for
chromatographic techniques.
Minor isomer: An NOE correlation was observed
between hydrogens HA and HB indicating that these
two protons were on the same side of the five-mem-
bered ring. Also, no NOE correlation was observed
between the acetyl CH3 and hydrogen HB. It was
therefore concluded that the minor diastereomer had
the acid and acetyl groups cis to each other.
2. Synthesis
The starting N-(2-hydroxy-2-methyl)but-3-enyl-N-ben-
zylamine 5 was prepared by heating benzylamine (41
mL, 0.375 mol) and 2-methyl-2-vinyloxirane (7.36 mL,
0.075 mol) at 80°C for 72 h. Chromatography on silica
gel gave N-(2-hydroxy-2-methyl)but-3-enyl-N-benzyl-
amine 5 (12.7 g, 89%) as a clear oil (Scheme 3).6
N-Benzyl-4-acetylproline 6 was prepared by adding gly-
oxylic acid monohydrate (3.71 g, 0.04 mole) to a stirred
solution of N-(2-hydroxy-2-methyl)but-3-enyl-N-benzyl-
amine (6.99 g, 0.036 mole) in methanol (25 mL). The
reaction mixture was stirred for 48 h and the solvent
removed under reduced pressure. Addition of ethyl
acetate gave a precipitate which was filtered to give
N-benzyl-4-acetylproline 6 (5.7 g, 64%) as a white solid
(Scheme 3).7 This reaction occurs at room temperature
and requires no purification which is in contrast to the
work by Overman et al. which required elevated tem-
peratures (50–100°C).4
3. Conclusion
N-Benzyl-4-acetylproline 6 can be prepared from N-(2-
hydroxy-2-methyl)but-3-enyl-N-benzylamine 5 and gly-
oxylic acid via
a
tandem cationic aza-Cope
reaction. This reaction
rearrangement-Mannich
requires only mild conditions and a good yield of
amino acid product is obtained without any need for
purification. The scope of this method is currently being
A mixture of two racemic products was expected and it
was observed from NMR analysis that a major
diastereomer was obtained.7 The ratio of diastereomeric
products varied between 80:20 and 96:4 depending on
reaction conditions (note this is a ratio of precipitated
products). NOE analysis was used to determine the
major and minor diastereomeric products obtained
(Fig. 1).
Figure 1. NOE correlations for the major and minor
diastereomers.
Scheme 3. Synthesis of N-benzyl-4-acetylproline 6.

A. Cooke et al. / Tetrahedron Letters 43 (2002) 903–905
905
extended to other functionalised and chiral hydroxy-
alkene-amines, and we intend to report the results of
these studies in the near future.
3. Bennett, D. J.; Hamilton, N. M. Tetrahedron Lett. 2000,
41, 7961–7964.
4. Overman, L. E.; Kakimoto, M.; Okazaki, M. E.; Meier,
G. P. J. Am. Chem. Soc. 1983, 105, 6622–6629.
5. Agami, C.; Couty, F.; Lin, J.; Mikaeloff, A.; Poursoulis,
M. Tetrahedron 1993, 49, 4039.
Acknowledgements
6. N-(2-hydroxy-2-methyl)but-3-enyl-N-benzylamine 5. 1H
NMR (400 MHz, CDCl3) l 7.35–7.22 (m, 5H, Ar-H), 5.80
(dd, J=11, 16 Hz, 1H, CH2CHC), 5.31 (d, J=16 Hz, 1H,
CH2CH), 5.09 (d, J=11 Hz, 1H, CH2CH), 3.80 (s, 2H,
PhCH2N), 2.71 (d, J=13 Hz, 1H, NCH2C), 2.51 (d, J=13
Hz, 1H, NCH2C), 1.22 (s, 3H, CH3C). ESI-MS (M+H)+
192.4.
The authors would like to thank the Analytical Chem-
istry Department, Organon Laboratories Ltd., New-
house, Scotland ML1 5SH, UK, for all analytical data.
1
7. N-Benzyl-4-acetylproline 6. H NMR (400 MHz, CDCl3)
major isomer (trans) l 7.41–7.23 (m, 5H, Ar-H), 4.29 (d,
J=13 Hz, 1H, PhCH2N), 3.92 (d, J=13 Hz, 1H,
PhCH2N), 3.72–3.64 (m, 1H, NCHCH2), 3.56–3.42 (m,
1H, NCH2CH), 3.38–3.23 (m, 1H, CH2CHCH2), 3.05 (m,
1H, NCH2CH), 2.58–2.3 (m, 2H, CHCH2CH), 2.19 (s, 3H,
CH3C). ESI-MS (M+H)+ 248.2. TOF accurate mass
248.1278.
References
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2057–2066.
2. (a) DeShong, P.; Kell, D. A.; Sidler, D. R. J. Org. Chem.
1985, 2309; (b) DeShong, P.; Kell, D. A. Tetrahedron Lett.
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